5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5h-(1)-benzopyrano(3,4-d)pyridine as an anti-diarrheal agent

ABSTRACT

A METHOD OF CONTROLLING DIARRHEA BY ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF 5,5-DIMETHYL-10-HYDROXY - 8 - (3 - METHYL-2-OCTYL)-2-(2-PROPYNYL)-1,2,3,4TETRAHYDRO-5H-(1) BENZOPYRANO (3,4-D) PYRIDINE TO A PATIENT IN NEED OF SUCH TREATMENT.

United States Patent O 5,5 DIMETHYL 10-HYDR0XY-8-(3-METHYL-2- OCTYL)2-(2-PROPYNYL)-1,2,3,4-TETRAHYDRO- SH-[l] BENZOPYRANO[3,4-d]PYRIDINE ASAN ANTI-DIARRHEAL AGENT Louis Selig Harris, Chapel Hill, N.C., and HarryGeorge Pars, Lexington, and Raj Kumar Razdan, Belmont, Mass, assignorsto Sharps Associates, Cambridge, Mass. No Drawing. Filed Aug. 24, 1972,Ser. No. 283,619

Int. Cl. A61k 27/00 US. Cl. 424-263 2 Claims ABSTRACT OF THE DISCLOSUREA method of controlling diarrhea by administering a therapeuticallyeffective amount of 5,5-dimethyl-10-hydroxy 8 (3methyl-2-octyl)-2-(2-propynyl)-l,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-d] pyridine to a patient in need ofsuch treatment.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a methodof controlling diarrhea using 5,5 dimethyl -hydroxy-8-(3-methyl-2-octyl) 2-(2-propynyl)1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine as theanti-diarrheal agent.

Morphine is one of the most potent agents known for controllingintestinal motility. However, morphine has two disadvantages; morphineis not active when administered orally and it is addicting. Therefore,while a single dose of morphine may be administered to stop severeepisodes of diarrhea, it is generally not the drug of choice. Paragoricis also used for the control of diarrhea; however, because of itsnarcotic liability, it cannot be used for chronic administration.

While there are a number of currently available therapeutic agents whichare useful in the treatment of acute episodes of diarrhea and withchronic episodes associated with colitis and the like, the search forimproved agents with fewer side effects continues. The present inventionprovides one such agent.

5,5 dimethyl 10 hydroxy-S-(3-methyl-2-octyl)- 2-(2 propynyl) 1,2,3,4tetrahydro 5H [1]benzo-' pyrano[3,4-d] pyridine has previously beenreported to be useful as a central nervous system depressant (see US.Pat. No. 3,576,798). It has now been found that the compound is usefulas an anti-diarrheal agent.

The compound useful in the practice of this invention is represented bythe formula CHr-CECH The compound can be prepared according to themethod taught in U.S. Pat. No. 3,576,798.

In the practice of this invention, oral dosages of from 0.005 to 10 mg./kg. of body weight daily is administered to patients suffering fromdiarrhea or excessive intestinal motility. While a single dose of thedrug can be administered to such patients, it is preferred to administerthe drug in divided dosages, i.e., theree to four times daily. While theoral route is preferred, the compound is also active by theintraperitoneally and can be administered via the intravenous or otherinjectable routes.

The following examples further illustrate this invention.

Example l.--Oral effects of 5,5-dimethyl-l0-hydroxy-8- (3 meth'yl2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro- 5H [1]benzopyrano[3,4d]pyridine on intestinal motility in mice Group of 10 femaleSwiss-Webster (Wisconsin) mice weighing 16-24 g. were fasted overnightand then given various oral doses of the compound 0 to 60 minutes priorto a charcoal meal. The compound was prepared as 0.00001 to 1%suspension in 0.5% methylcellulose.

Through the use of serial dilutions from the 1% suspension, it waspossible to maintain the maximum volume given at 10 cc./kg. The charcoal(Norit) was prepared as a 5% suspension in 0.5% methylcellulose andadministered at a volume of 0.25 cc. per mouse. Thirty minutes after themeal, the animals were sacrificed with chloroform. The digestive tract(stomach to colon) was removed. A three gram weight was hung from thecolon for 20 seconds. The length of the small intestines and thedistance that the meal had travelled were measured.

Methylcellulose alone and morphine were also evaluated.

As can be seen from the following Table I, 5,5-dimethyl- 10 hydroxy 8 (3methyl-Z-octyl)-2-(2-propynyl)- 1,2,3,4 tetrahydro5H-[1]benzopyrano[3,4-d]pyridine is more potent than morphine sulfate inslowing intestinal motility in mice. In the table,5,5-dimethyl-l0-hydroxy- 8 (3 methyl2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d1pyridineis designated as A, morphine sulfate as B and methylcellulose as C.

TABLE I Time 0', avg. Time 60, avg. Dose, percent travelled percenttravelled mg./kg. (range) (range) Compound:

A O. 0005 64 (45. 1-86. 3) 73. 3 (56. 5-93. 3) 0. 001 55. 3 (31. 5-78.8) 70. 3 (34. 7-100) 0. 0025 61. 2 (42. 5-100) 66. 4 (44-100) 0. 005 53.7 (43. 7-74. 7) 54. 8 (42. 3-85. 5) 0. 01 55. 4 (29. 2-88. 3) 50 (38.6-69. 7) 0. 1 40. 4 (25-54. 33. 1 (20. 8-46) 1. (l 38. 8 (27. 7-52. 2)37. 3 (16. 7-88) 10. 0 39 (29. 5-59. 5) 18. 3 (5. 67-41. 7) 100. 0 28. 2(17. 3-41. 8. 4 (2. 1-12. 2) 1 5 (46-92) 66. 8(51. 8-87) 10 42 (6-6 656) 20 46 (25-79) 50 (17-100) 40 41 (24-95) 35 (20-66) 72. 8 (55-92. 7)74. 6 (59. 3-85. 4)

l 10 cc.[kg.

Example 2.-Oral effect of 5,5-dimethyl-10-hydroxy-8-(3- methyl 2 octyl)2-(2-propynyl)-l,2,3,4-tetrahydro- 5H [1]benzopyrano[3,4 d]pyridine andmorphine sulfate on intestinal motility in mice (5 day study) Groups of10 female Swiss-Webster (Wisconsin) mice 16-24 g. were given 0.1 or 1mg./kg. of 5,5-dimethyl-10- hydroxy (3methoxy-Z-octyD-Z-(2-propynyl)-1,2,3,4- tetrahydro 5H [1]benzopyrano[3,4d]pyridine for 5 days. Similarly, groups of mice were given 1 or 10 mg./kg. of morphine sulfate on the above dosage schedule. The animals werefasted between the 4th and 5th dose of the drugs. On day 5, the drug wasadministered 0 or 60 minutes prior to a charcoal meal (5% Norit charcoalin 0.5% methylcellulose). The meal was administered at a volume of 0.25cc./mouse. Thirty minutes after the mea the animals were sacrificed withchloroform. The digestive tract (stomach to colon) was removed and a 3g. weight was hung from the colon for 20 seconds. The length of thesmall intestines and the distance that the meal had travelled weremeasured. A control group (10 cc./kg., 0.5% methylcellulose) was dosedin the same manner as the test animals. 5,5- dimethyl 10 hydroxy 8(3-methyl-2-octyl)-2-(2- propynyl) 1,2,3,4 tetrahydro 5H [l]benzopyrano[BA-d]pyridine was prepared as 0.001 and 0.01% suspensions Whilemorphine sulfate was prepared as 0.01 and 0.01% solutions. Both drugswere in 0.5% methylcellulose. Compounds are designated A, B and C, as inEX- ample 1, in Table II.

l 10 ccJkg.

The above data indicate there is some tolerance developed for both5,5-dimethyl-10-hydroxy-8-(3-methy1-2- octyl) 2 (2 propynyl)-1,2,3,4tetrahydro-5H-[1] benzopyrano-[3,4-d]pyridine and morphine sulfate whenadministered for 5 consecutive days; however, there is somewhat lesstolerance developed for the compound useful in the practice of thisinvention than for morphine sulfate.

The compound useful in the practice of this invention can be formulatedinto various pharmaceutically acceptable dosage forms such as tablets,capsules, pills and the like for immediate or sustained release, bycombining the compound with a suitable pharmaceutically acceptablecarrier or diluent according to methods well known in the art. Suchdosage forms may additionally include lubricants, cxcipients, binders,fillers, flavoring and sweetening agents and other therapeutically inertingredients necessary for the formulation of the desired preparation.

We claim:

1. A method of controlling diarrhea by administering a therapeuticallyeffective amount of 5,5-dimethyl-10-hydroxy 8 (3methyl-Z-octyl)2-(2-propynyl)-1,2,3,4- tetrahydro 5H[1]benzopyrano[3,4-d]pyridine to a patient in need of such treatment.

2. A method in accordance with claim 1 wherein 5,5- dimethyl 10 hydroxy8-(3 methyl-2-octyl)-2-(2- propynyl) 1,2,3,4 tetrahydro5H-[1]benzopyrano- [3,4-d]pyridine is administered in dosages of from0.005 to 10.0 mg./kg. of body weight daily.

References Cited UNITED STATES PATENTS 3,576,798 4/1971 Pars et a1.260-240 K STANLEY J. FRIEDMAN, Primary Examiner Patent No. 3'777!028Dated December 4, 973

Louis Selig; Harris et a1.

Inventor(s) sin the above-identified patent It is certified that errorappear shown below:

and that said Letters Patent are hereby corrected as hange thesubstituent at the right Column 1, lin 5 0 u I! C H la from 6 to 5 1 endof the structural formu Column 2, line 53, change "hydrox (3-methoxy-Z-octyl) to --hydroxy-8-(B-methoxy-Z-octyl Signed and sealedthis 25th day of June 197 4.

(SEAL) Attest:

EDWARD M.FLETCHER, JR. c. MARSHALL DANN Attesting Officer Commissionerof Patents FORM PC4050 (10-69) w: usv GOVERNMENT PRINTING OFFICE: I969o--3sssu.

